Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease such as arteriosclerosis. To date, there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG--CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof. The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein: Z is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino;
R is: ##STR3## wherein Q is ##STR4## R.sub.2 is H or OH; R.sub.1 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds. PA0 R.sup.1 is C.sub.1-3 alkyl; PA0 R.sup.2 is hydrogen or C.sub.1-3 alkyl; PA0 R.sup.3 and R.sup.4 independently are hydrogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl, phenyl or PA0 R.sup.5 is hydrogen or hydroxy; PA0 X and Y independently are hydrogen, halogen (F, Cl or Br), trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or a group selected from: PA0 A is ##STR13## in which R.sup.12 is hydrogen or hydroxy; B is CHR.sup.13 in which R.sup.13 is hydrogen or hydroxy; and PA0 a, b, c and d represent single bonds, one of a, b, c or d represents a double bond, both a and c or both b and d represent double bonds provided that when a is a double bond, A is ##STR14## and when d is a double bond, B is ##STR15## and Z is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino or acetylamino; PA0 (1) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethylphenylacetyloxy)-2(S),6(R)-dimethyl -1,2,6,7,8,8a-(R)-hexadhydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetra hydro-2H-pyran-2-one; PA0 (2) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethyl-4'-hydroxyphenylacetyloxy)-2(S),6( R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4, 5,6-tetrahydro-2H-pyran-2-one; PA0 (3) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethyl-3'-hydroxy-phenylacetyloxy)-2(S),6 (R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4 ,5,6-tetrahydro-2H-pyran-2-one; PA0 (4) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethyl-4'-hydroxymethylphenylacetyloxy)-2 (S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydrox y-3,4,5,6-tetrahydro-2H-pyran-2-one; PA0 (5) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethyl-4'-hydroxy-3'-fluorophenylacetylox y)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hy droxy-3,4,5,6-tetrahydro-2H-pyran-2-one; PA0 (6) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethyl-4'-methoxyphenylacetyloxy)-2(S),6( R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4, 5,6-tetrahydro-2H-pyran-2-one; and PA0 (7) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethyl-4'-ethoxyphenylacetyloxy)-2(S),6(R )-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5 ,6-tetrahydro-2H-pyran-2-one. PA0 (1) 6(R)-[2-[8(S)-(.alpha.,.alpha.-dimethyl-3-phenylpropionyloxy)-2(S),6(R)-di methyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-t etrahydro-2H-pyran-2-one; PA0 (2) 6(R)-[2-[8(S)-[.alpha.,.alpha.-dimethyl-3-(4'-hydroxyphenyl)-propionyloxy] -2(S),6(R)-dimethyl-1,2,6,7,8,8a(R) -hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2- one; and PA0 (3) 6(R)-[2-[8(S)-[.alpha.,.alpha.-dimethyl-3-(3',5'-dihydroxyphenyl)-propiony loxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
U.S. Pat. No. 4,517,373 discloses semi-synthetic compounds represented by the above general formula wherein R is ##STR5##
U.S. Pat. No. 4,346,227 and U.S. Pat. No. 4,448,979 also disclose semi-synthetic compounds represented by the above general formula wherein R is ##STR6##
Japanese unexamined patent application No. J59-122,483-A discloses a semi-synthetic compound represented by the above general formula wherein R is ##STR7## in which R.sub.3 is hydrogen or methyl; R.sub.4 is hydrogen, halogen or haloalkyl; R.sub.5 is hydrogen, halogen or lower alkyl and R.sub.6 is halogen, N.sub.3, hydroxy, thio, amino, lower alkoxy, lower alkylthio and aralkylthio.
U.S. Pat. No. 4,444,784 discloses 8'-acyloxy derivatives of compactin, mevinolin and the dihydro and tetrahydro analogs thereof. Generically disclosed are the phenyl containing compounds represented by the above general formula wherein R is: ##STR8## in which R.sub.7 is hydrogen or methyl and R.sub.8 is phenyl-C.sub.1-3 alkyl or substituted phenyl-C.sub.1-3 alkyl in which the substituent is halo, C.sub.1-3 alkyl or C.sub.1-3 alkoxy.